A “Capture-and-Lock” Ozone-Reservoir Hydrogel for Rheumatoid Arthritis Therapy

Abstract Rheumatoid arthritis (RA) is a chronic autoimmune disease driven by excessive reactive oxygen species (ROS) and M1 polarization, leading to synovial inflammation and bone destruction. Current immunosuppressants cannot target these core mechanisms and cause severe side effects. Ozone shows potential for RA treatment via anti-oxidant and anti-inflammatory effects, but its instability, rapid diffusion, and short retention severely limit clinical efficacy. Herein, we develop an injectable ozone-reservoir hydrogel (O3@F@OHC) by covalently incorporating perfluorinated polymer (PFAM) into a Schiff-base crosslinked network of oxidized hyaluronic acid and carboxymethyl chitosan. The hydrogel achieves stable ozone loading and sustained release for over 48 h through a “capture-and-lock” mechanism, with PFAM acting as an efficient “ozone sponge”. This hydrogel also exhibits favorable self-healing, biocompatibility, and adaptive biodegradability. In vitro, ozone released from O3@F@OHC hydrogel could activate endogenous antioxidant defense system, thereby enhances cellular antioxidant capacity, eliminates excessive intracellular free radicals, downregulates inducible nitric oxide synthase (iNOS) expression, and ultimately exerts anti-inflammatory effects. In rats with collagen-induced arthritis, this hydrogel alleviates synovial inflammation and bone destruction. This work provides a promising strategy for ozone-based intra-articular therapy of RA.